Photo Credit: Akram Huseyn
Scientific Frontline: Extended "At a Glance" Summary: Novel Treatment for Acute Myeloid Leukemia
The Core Concept: Researchers have developed a novel therapeutic approach that combats acute myeloid leukemia (AML) by forcing the cancer cells to maintain a state of high activity while simultaneously cutting off their energy supply, causing them to die from metabolic stress.
Key Distinction/Mechanism: Unlike traditional methods that focus on damaging DNA, this treatment targets cancer metabolism. A newly designed molecule called AcTor stimulates the mTor protein, a cellular control center, to promote continuous cell growth and activity. Concurrently, a standard anti-proliferative drug (Ixazomib) shuts down energy production in the mitochondria. This dual action—pushing the accelerator while applying the brake—induces fatal stress in the cancer cells without harming healthy blood cells or triggering drug resistance.
Major Frameworks/Components:
- AcTor: A newly designed molecule that inhibits a signaling protein to stimulate mTor.
- mTor Protein: A cellular control center regulating growth, maintenance, and rest.
- Mitochondria: The energy-producing structures within cells, targeted for shutdown by the treatment.
- Ixazomib (IXZ): An inhibitor used in combination with AcTor to block energy production.
- ADM2 Protein: Released during the treatment, potentially serving as a biomarker for clinical response.
Branch of Science: Biochemistry, Physical Chemistry, Computational Chemistry, and Oncology.
Future Application: The method aims to proceed through preclinical and clinical trials to offer a viable treatment for patients with relapsed or refractory AML, including highly aggressive forms like TP53-mutant AML. The identification of ADM2 as a biomarker could also guide future translational and clinical studies.
Why It Matters: AML is an aggressive and often fatal cancer with limited treatment options, particularly for relapsed or mutant variations. This new method not only eliminates diseased blood cells but also eradicates leukemic stem cells (which cause relapses) and avoids triggering drug resistance, representing a significant shift towards metabolic cancer treatments.
Pushing the accelerator and the brake at the same time is rarely a good idea. But researchers at the University of Gothenburg are using this approach to treat leukemia. A new drug forces cancer cells to keep working hard without energy until they die. The first study in mice shows very promising results.
A team led by Leif Eriksson at the University of Gothenburg and Boaz Tirosh at Case Western Reserve University in Cleveland has developed a new treatment for acute myeloid leukemia (AML). AML is an aggressive form of cancer affecting the blood and bone marrow, which prevents the production of red and white blood cells. The disease, which affected about one million people globally in 2015, requires immediate treatment and primarily affects adults.
Different Areas of Expertise
“Boaz Tirosh is a biochemist and understands the processes taking place within a cell. It was he who put forward the hypothesis for this treatment. I am a computational chemist and have designed a molecule that enters the cancerous cell and alters it in the way we want,” says Leif Eriksson, professor of physical chemistry at the University of Gothenburg.
The molecule, named AcTor, inhibits a signaling protein that affects the function of the mTOR protein. The mTOR protein acts as a control center that determines when the cell should grow, build itself up, or rest. The researchers’ intervention ensures that mTOR continues to promote full cell activity, even though energy production in the mitochondria is shut down using a standard antiproliferative drug. The combination of treatments means that the cancer cells continue to press the accelerator even while the brake is on. This causes the cells to run amok and die from stress.
“It’s a completely new method and does not affect healthy blood cells; furthermore, our studies in mice show that drug resistance is avoided, which can otherwise happen,” says Leif Eriksson.
Leukemic Stem Cells Disappeared
The study, published in Molecular Cancer, reports that AcTor had a very strong effect on leukemia in both AML cell lines and primary patient samples, as well as in animal trials, when used in combination with the inhibitor ixazomib (IXZ). The treatment remained equally effective in TP53-mutant AML, a highly aggressive form of cancer with a poor prognosis and limited treatment options. Not only were diseased blood cells eliminated using the new method, but leukemic stem cells—which can lead to relapse—also disappeared.
“We also observed that our treatment triggered the release of a protein (ADM2), which could therefore serve as a biomarker for the treatment’s response. This could guide future translational and clinical studies,” says Leif Eriksson.
Validation in Preclinical Studies
Work is now continuing to validate the treatment in preclinical and, eventually, clinical studies. There is still a long way to go before this method is ready to treat patients with relapsed or refractory acute myeloid leukemia, who currently face limited options and a poor prognosis.
“Our study is an example of the shift toward focusing research on cancer metabolism within cells, rather than relying solely on methods that damage DNA. Drug development is very expensive, but we hope that our findings will generate sufficient interest to enable us to continue our research into a cure for this serious disease,” says Leif Eriksson.
Published in journal: Molecular Cancer
Title: AcTor, a novel mTOR stimulator, potentiates ixazomib for the treatment of acute myeloid leukemia
Authors: Shakti P Pattanayak, Odai Darawshi, Omid Hajihassani, Jordan M Winter, Nicole Weiler, Melanie Ott, Florian Rothweiler, Jindrich Cinatl Jr., Martin Michaelis, Daniel J Lindner, Thomas D Green, Polina Krassovskaia, Raphael T Aruleba, Kelsey H Fisher-Wellman, Jason A Mears, David Wald, Leif A Eriksson, and Boaz Tirosh
Source/Credit: Göteborgs Universitet
Edited by: Scientific Frontline
Reference Number: bchm090826_01
